Clinical and genomic landscape of <i>EGFR</i>-mutant lung cancers (LCs) with squamous and adenosquamous differentiation.
Authors: Arielle Elkrief, Christina J. Falcon, Allison L. Richards, Alexandria Dymun, Paul K. Paik, Rania G. Aly, Natasha Rekhtman, Charles M. Rudin, Alvaro Quintanal-Villalonga, Helena Alexandra Yu
Journal: Journal of Clinical Oncology (2023)

9129 Background: Outcomes to first-line therapy with osimertinib in patients (pts) with EGFR-mutant (EGFR+) squamous (sq) or adenosquamous (adenosq) LC have not been well described. Pts also undergo adenocarcinoma to squamous transformation (transformed) after treatment with EGFR tyrosine kinase inhibitor (TKI). The clinical and genomic characteristics of pts with EGFR+ sq and adenosq LC are largely unknown. Methods: We clinically and genomically characterized all pts with EGFR+ LC with baseline sq or adenosq histology and transformed histology at Memorial Sloan Kettering Cancer Center. Next-generation sequencing was performed with the MSK-IMPACT. We compared clinical outcomes (time to discontinuation (TTD), overall survival (OS), and post-progression survival after osimertinib discontinuation (PPS)) among the different cohorts. Results: A total of 51 pts were identified: 14 with baseline sq/adenosq treated with first-line (1L) osimertinib; 8 transformed cases post 1L osimertinib; 13 with baseline sq/adenosq treated with early generation TKI; 3 transformed cases post early generation TKI; the remainder of pts had early-stage EGFR+LC with baseline sq/adenosq. Median age was 63, and 57% were female. Eighteen (35%) were former or current smokers. Among pts with baseline sq/adenosq histology who were treated with 1L osimertinib, median TTD was 11.1 months (95%CI 7.7, not reached (NR)), and median OS was 24.3 months (95%CI 11.1 months, NR). Compared to a non-overlapping time-matched cohort with baseline adenocarcinoma treated with 1L osimertinib (N = 55), TTD was numerically shorter in the sq/adenosq cohort (11 vs. 17 months, HR 1.8, p = 0.076), and median OS was significantly shorter (24 vs. 33 months, HR 2.64, p = 0.03). PPS was shortest in baseline sq/adenosq (5 months, HR 2.94, p = 0.023), but similar in transformed (11 months, HR 0.89, p = 0.8) compared to adeno (11 months). The sq/adenosq cohort had significantly higher proportion of L858R EGFR (48% vs 31% p &lt; 0.001) and atypical EGFR mutations at baseline (17% vs 7.3%, p &lt; 0.001) compared to the adenocarcinoma cohort. PIK3CA mutations were enriched at baseline in the sq/adenosq cohort. In the transformed cases, RB1 alterations were present in 13% at baseline. There was a similar distribution of type of EGFR mutations in the non-overlapping pts in the AACR GENIE EGFR+ LC cohort with sq/adenosq histology (N = 4, 50% L858R, 25% atypical). Conclusions: Pts with EGFR+ sq/adenosq LCs exhibit inferior TTD and OS with 1L osimertinib compared to adenocarcinoma controls. Sq/adenosq LCs appear to be molecularly distinct with enrichment in EGFR L858R and atypical EGFR mutations. Transcriptomic profiling of a subset of samples will be presented. Our findings highlight the need for novel therapeutic strategies among pts in this high-risk subgroup.